Project Summary/Abstract Cell-type specific manipulation of neural circuits is required for the treatment of neurological disorders such as epilepsy and Parkinson?s disease. Precise control of neural circuits will enable the development of neuromodulation therapies for these debilitating conditions. Existing technologies to control neural activity offer limited possibilities. Manipulation of brain circuits via direct drug treatment is restricted by the selective permeability of the blood-brain barrier, the rapid clearance of cerebral fluids and the lack of specificity which results in poor response to drugs and undesirable side effects. Electrical stimulation and optogenetics have open the possibility of repairing neural dysfunction through direct control of brain circuit dynamics. However, both technologies require implantable devices that are damaging to biological tissues. Recently, the heat dissipation by nanomaterials, particularly magnetic nanoparticles (MNPs) and plasmonic nanostructures, has been proposed for the wireless control of cellular signaling using external stimuli. The weak magnetic properties and low electrical conductivity of tissue allow alternating magnetic fields (AMFs) to reach deep into the body, making hysteresis heating of MNPs particularly promising for the treatment of brain disorders. This research grant will develop a novel wireless pharmacological brain stimulation approach that depends on magnetic nanoparticles (MNPs) heating effects to release neuromodulatory compounds from temperature-sensitive polymers grafted on the surface of MNPs. The developed technology will be suitable for drug release in multiple on-demand dosages, which it is required for neural activity stimulation. Additionally, we will tailor polymer surface chemistry for the combinatorial release of neurostimulator-inhibitor pairs to allow modulation of brain circuit signals. Preliminary results demonstrate: 1) the heat dissipated by MNPs under AMFs is sufficient for the rapid and complete release of a payload from MNP surfaces, 2) MNPs targeting to neuronal membranes via antibody specificity, followed by magnetothermal drug treatment that allows for one-time excitation of neural activity, and 3) the precise control of polymer growth from the surface of MNPs. This research grant drives new advances in stimuli-responsive hybrid nanoparticle systems for the pharmacological modulation of neural activity. Wireless magnetothermal release of dopamine and chlorpromazine from polymer coated MNPs is expected to excite and inhibit activity of dopaminergic neurons. This system will be optimized for on-demand multiple dosages release by triggering heat response with AMFs. Finally, the functional properties of clinically-relevant neural modulation by magnetothermal drug release will be evaluated through in vitro assays. Magnetothermal modulation of neural activity shows considerable promise as a powerful pharmacological technology that can be applied to restore brain functions, and in single-cell manipulation settings for the better understanding of neural circuits. Future directions of this work include the development of a magnetothermal platform that allow in vivo pharmacological modulation of neural activity.